Genetic Diseases of Mitochondrial

originNISHA K SUNNYMSc BIOTECHNOLOGY

GENETIC DISEASESCYTOCHROME C OXIDASE

DEFEICENCYLEIGH SYNDROMEKEARN SYARE SYNDROMELOHN NON SYNDROMIC DEAFNESSMYOPATHY RETINOPATHY

CYTOCHROME C OXIDASE (complex IV deficiency) Mutations in at least 14 mitochondrial genes

The mitochondrial genes associated with cytochrome c oxidase deficiency provide instructions for making subunit proteins that are part of a large enzyme complex called cytochrome c oxidase

• Cytochrome c oxidase is responsible for the last step in oxidative phosphorylation before the generation of ATP.

• The mitochondrial DNA mutations that cause this condition alter the subunit proteins that make up cytochrome c oxidase

• cytochrome c oxidase cannot function

• A lack of functional cytochrome c oxidase disrupts the last step of oxidative phosphorylation, causing a decrease in ATP production

• impaired oxidative phosphorylation can lead to cell death in tissues that require large amounts of energy, such as the brain, muscles, and heart.

• Signs and symptoms: begin before age 2 but can appear later in mildly affected individuals.

• People who are mildly affected tend to have (myopathy) and (hypotonia)

• Severely affected people have myopathy along with (encephalomyopathy)

• An enlarged liver, lactic acidosis

• fatal in childhood, although some individuals with mild signs and symptoms survive into adolescence or adulthood.

• have a type of heart disease that enlarges and weakens the heart muscle hypertrophic cardiomyopathy

• specific group of features known as Leigh syndrome

Leigh syndrome

• Mutations in one of several different mitochondrial genes can cause Leigh syndrome

• progressive brain disorder that usually appears in infancy or early childhood

• Some of the genes associated with Leigh syndrome provide instructions for making proteins that are part of the large enzyme complexes necessary for oxidative phosphorylation

• Some of the genes associated with Leigh syndrome provide instructions for making proteins that are part of the large enzyme complexes necessary for oxidative phosphorylation

• the most commonly mutated mitochondrial gene in Leigh syndrome, MT-ATP6, provides instructions for a protein that makes up one part of complex V

• an important enzyme in oxidative phosphorylation that generates ATP in the mitochondria.

• other genes provide instructions for making tRNA molecules, which are essential for protein production within mitochondria

• mitochondrial gene mutations that cause Leigh syndrome impair oxidative phosphorylation

• impaired oxidative phosphorylation can lead to cell death in sensitive tissues, which may cause the signs and symptoms of Leigh syndrome

• Signs and symptoms: loss of mental function, movement problems, hypertrophic cardiomyopathy, eating difficulties, and brain abnormalities.

• Cytochrome c oxidase deficiency is one of the many causes of Leigh syndrome.

• changes in mitochondrial DNA• Some of the genetic changes alter single DNA

building blocks (nucleotides)• whereas others rearrange larger segments of

mitochondrial DNA.• These changes likely impair the ability of

mitochondria to produce energy

• impaired mitochondria may affect certain cells of the autonomic nervous system

• nervous system that controls involuntary body functions such as heart rate, blood pressure, and digestion

• CVS typically develops during childhood, usually between ages 3 and 7; although it often remits during adolescence, it can persist into adult life.

• Signs and symptoms: • recurring attacks of intense nausea, vomiting and

sometimes abdominal pain, headaches or migraines.

• There is no known cure for CVS, but there are medications that can be used for treatment, intervention, and prevention

Kearns-Sayre syndrome

• oculocraniosomatic disorder or Oculocraniosomatic neuromuscular disorder

• mitochondrial myopathy with a typical onset before 20 years of age

• Most people with Kearns-Sayre syndrome have a single, large deletion of mitochondrial DNA

• The deletions range from 1,000 to 10,000 nucleotides, and the most common deletion is 4,997 nucleotides

• primarily affects the eyes, causing weakness of the eye muscles (ophthalmoplegia) and breakdown of the light-sensing tissue at the back of the eye (retinopathy).

• KSS involves a triad of Chronic progressive external ophthalmoplegia (CPEO), as well as bilateral pigmentary retinopathy, and cardiac conduction abnormalities.

• The mitochondrial DNA deletions result in the loss of genes that produce proteins required for oxidative phosphorylation

• causing a decrease in cellular energy production.• eyes are commonly affected by mitochondrial

defects because they are especially dependent on mitochondria for energy.

• cerebellar ataxia, proximal muscle weakness, deafness, diabetes mellitus, growth hormone deficiency, hyperparathyroidism, or other endocrinopathie

Leber hereditary neuropathy

• Mitochondrially inherited diseases• degeneration of retinal ganglion cells• Lohn is usually due to:• Mutations in four mitochondrial genes, MT-ND1, MT-

ND4, MT-ND4L, and MT-ND6• These genes provide instructions for making proteins

that are part of a large enzyme complex• This enzyme, known as complex I, is necessary for

oxidative phosphorylation

• The mutations responsible for Lohn change single amino acids in these proteins, which may affect the generation of ATP within mitochondria.

• mutations are often limited to the nerve that relays visual information from the eye to the brain (the optic nerve).

• Vision in Lohn patients is weird.

Pearson marrow-pancreas syndrome

• deletion of mitochondrial DNA

• The size and location of mitochondrial DNA deletions vary, usually ranging from 1,000 to 10,000 nucleotides

• It’s the same deletions present in the Kearns-Sayre syndrome later in life.

• This severe condition affects the development of blood cells and the function of the pancreas and other organs

• Mitochondrial DNA deletions lead to the specific signs and symptoms of Pearson marrow-pancreas syndrome

• Some individuals with Pearson marrow-pancreas syndrome who survive past early childhood develop signs and symptoms of Kearns-Sayre syndrome later in life.

• Affected individuals have (anemia, pallor, weakness, fatigue, neutropenia, thrombocytopenia)

• reduced ability to absorb nutrients from the diet (malabsorption)

• most affected infants have an inability to grow and gain weight at the expected rate (failure to thrive).

• Another common occurrence in people with this condition is buildup in the body of a chemical called lactic acid lactic acidosis

Nonsyndromic deafness

• Mutations in two mitochondrial genes, MT-RNR1 and MT-TS1

• These genes provide instructions for making different types of RNA.

• The MT-RNR1 gene provides instructions for a specific type of ribosomal RNA called 12S RNA

• A particular form of tRNA, designated as tRNASer(UCN), is formed from the MT-TS1 gene

• Both of these RNA molecules help assemble amino acids into full-length, functioning proteins within mitochondria

• Mutations in the MT-RNR1 gene increase the risk of hearing loss, particularly in people who take prescription antibiotic medications called amino glycosides

• Amino glycosides kill bacteria by binding to their ribosomal RNA and disrupting the bacteria's ability to make proteins

• Common genetic changes in the MT-RNR1 gene can make the 12S RNA in human cells look similar to bacterial ribosomal RNA.

• amino glycosides can target the altered 12S RNA just as they target bacterial ribosomal RNA.

• Reduce the production of proteins needed for oxidative phosphorylation, which may impair the ability of mitochondria to make ATP.

• the effects of mutations in the MT-RNR1 and MT-TS1 genes are usually limited to cells in the inner ear that are essential for hearing.